Parkinson's disease (PD) results from the death of dopaminergic neurons in the substantial nigra pars compacta (SNc) of the basal ganglia (BG). Replacement of lost dopamine is the standard PD treatment and is achieved by administering the dopamine precursor L-DOPA or dopamine receptor agonists. Dopamine replacement therapies, however, cause severe side effects and eventually lose efficacy in many patients. Increased understanding of neurocircuitry within the BG has led to the development of new therapeutic strategies to correct BG deficits and treat PD patients. The metabotropic glutamate receptors (mGlus) regulate synaptic transmission at several critical BG synapses and have potential as novel targets for PD treatment. Exciting translational advances have recently been made for mGlus 4 and 5 by integrating discovery and detailed molecular analyses of novel mGlu ligands with electrophysiological and behavioral studies. We have now generated preliminary data suggesting that mGlu8 may also regulate activity in the BG motor circuit and have potential utility as a novel target for non-dopaminergic PD treatments. Previous studies have suggested that activation of mGlu8 does not reverse motor impairments in acute PD models. However, our preliminary studies here show that activation of mGlu8 has robust antiparkinsonian activity in animals that have undergone prolonged dopamine depletion or blockade, suggesting that mGlu8 may represent a new target that could be manipulated once PD progression begins. However, highly selective activators of mGlu8 with properties suitable for optimization as drug candidates have been unavailable to further advance the hypothesis that mGlu8 activation may have therapeutic benefit in PD. Based on the high conservation of the glutamate binding site, it has been difficult to develop ligands with high selectivity and suitable pharmacokinetic properties that bind at the orthosteric site. Building upon a strategy we have used for other mGlus, we have recently developed a positive allosteric modulator (PAM) of mGlu8, VU0155094, which is highly selective for mGlu8 versus mGlu4. mGlu4 is a related glutamate receptor that also mediates effects in the basal ganglia; selectivity of VU0155094 for mGlu8 over mGlu4 indicates that we now have an appropriate tool compound to begin validating a role of mGlu8 in prolonged dopamine depletion models of PD. We will test the hypothesis that VU0155094 will modulate mGlu8-meditated synaptic transmission at synapses known to respond to mGlu8 agonists in brain slices. Additionally, we will test the hypothesis that mGlu8 PAMs, like mGlu8 agonists, have anti-PD effects in rodent models of prolonged dopamine depletion. PUBLIC HEALTH RELEVANCE: We have preliminary data showing that an agonist of metabotropic glutamate receptor 8 (mGlus) exhibits antiparkinsonian activity after prolonged, but not acute, dopamine depletion. We will test the hypothesis that a newly discovered positive allosteric modulator of mGlu8 will potentiate known mGlu8-mediated responses at specific brain synapses. We will then assess the ability of this mGlu8 PAM to exhibit antiparkinsonian activity in several rodent models of Parkinson's disease.